Key Points

  • Rapid uptake of mAb-opsonized cells by macrophages causes a persistent reduction of phagocytosis (hypophagia) due to reduced surface FcRs

  • As macrophages are key immune effectors for many therapeutic mAbs, hypophagia could contribute to therapeutic resistance to these mAbs.

Macrophage antibody dependent cellular phagocytosis (ADCP) is a major cytotoxic mechanism for both therapeutic unconjugated monoclonal antibodies (mAb) such as rituximab, and antibody induced hemolytic anemia and immune thrombocytopenia. Here, we studied the mechanisms controlling the rate and capacity of macrophages to carry out ADCP in settings of high target to effector cell ratio such as that seen in patients with circulating tumor burden in leukemic phase disease. Using quantitative live-cell imaging of primary human and mouse macrophages we found that, upon initial challenge with mAb-opsonized lymphocytes, macrophages undergo a brief burst (<1hr) of rapid phagocytosis which is then invariably followed by a sharp reduction in phagocytic activity that can persist for days. This previously unknown refractory period of ADCP, or "hypophagia," was observed in all macrophage/mAb/target cell conditions tested in vitro, and was also seen in vivo in Kupffer cells from mice induced to undergo successive rounds of ⍺CD20 mAb-dependent clearance of circulating B cells. Importantly, hypophagia had no effect on antibody-independent phagocytosis and did not alter macrophage viability. In mechanistic studies we found that the rapid loss of activating Fc receptors from the surface and their subsequent proteolytic degradation is the primary mechanism responsible for the loss of ADCP activity in hypophagia. These data suggest hypophagia is a critical limiting step in macrophage-mediated clearance of cells via ADCP and that understanding such limitations to innate immune system cytotoxic capacity will aid in the development of mAb regimens that could optimize ADCP and improve patient outcome.

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